DETAILED ACTION
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
2. Applicant's preliminary amendment filed on 09/18/2023 is acknowledged.
Claims 14-16, 18-19 and 25-39 are pending.
3. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION. —The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
4. Claims 14-16 and 18-19 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
(i) Claims 14 and 16 are indefinite in the use of the term “preferably,” because it is unclear whether or not the preferred embodiments constitute claim limitations. Description of examples or preferences is properly set forth in the specification rather than the claims.
(ii) Claim 15 is indefinite in the recitation of a nucleic acid sequence “codon-optimized for expression,” because the biological species to which the sequence is optimized is unknown.
(iii) Claims 18-19 are indefinite, because they encompass the indefinite limitations of the claim(s) on which they depend.
In view of the above, a person of ordinary skill in the art cannot unequivocally interpret the metes and bounds of the claims so as to understand how to avoid infringement. Applicant is reminded that any amendment must point to a basis in the specification so as not to add New Matter. See MPEP 714.02 and 2163.06.
5. The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
6. Claim 38 is rejected under 35 U.S.C. 112(a) as failing to comply with the enablement requirement. The claim contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The specification does not provide a sufficient enabling description of method for treating a generically recited “inflammatory disorder” comprising administering a PD-L1 [encoding] expression vector to the gastrointestinal tract of the patient.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized in In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, limited working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to make and use the claimed invention.
The claims encompass treatment of any inflammatory disorder, without limitation. The method comprises a single step, wherein a PD-L1-expressing vector is administered to the patient’s gastrointestinal tract.
According to the specification, the invention employs localized intestinal expression of PD-L1 for the treatment of inflammatory disorders “including, e.g., inflammatory bowel disease (e.g. ulcerative colitis, Crohn's disease, and the like) as well as graft-versus-host disease (GvHD) induced by organ or bone marrow transplant” [0005]. Inflammatory disorders that can be treated by claimed method “include both chronic and acute conditions, including inflammation associated with infection (e.g. septic shock, sepsis, or systemic inflammatory response syndrome (SIRS)), ischemia-reperfusion injury, endotoxin lethality, inflammatory bowel disease, Crohn's disease, colitis, or resulting from over production of cytokines (e.g. TNF or IL-1) as well as GvHD” [0011], [0086].
The specification further describes a working example of treating a mouse model of GvHD induced by bone marrow transplant (Example 6) and a working example of treating a mouse model of T-cell induced colitis (Example 7). The specification does not appear to provide guidance, direction, or working examples of any inflammatory diseases other than the mouse models in Examples 6 and 7.
Since the claimed method is based on “localized intestinal expression of PD-L1” [0005], it is not expected to affect organs or tissues outside of the gastrointestinal tract. A person of skill in the art would have been aware that “inflammatory disorders” is a very broad category encompassing numerous pathological conditions, only a miniscule fraction of which involve intestinal tissues. To name just a few, inflammation affects neural tissue in multiple sclerosis, joints in rheumatoid arthritis, skin in bacterial skin infections, and airways in bronchitis. Therefore, an ordinary artisan would readily recognize that treating the category of inflammatory diseases as broadly claimed by the recited method would almost certainly be unsuccessful and dangerous, and as such unnecessary, improper, and undue.
7. The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
8. Claims 14-16 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Mozaffarian et al. (US 20090110667).
Mozaffarian teaches administering a PD-L1-encoding nucleic acid which is codon optimized (i.e. comprising synonymous substitutions) for expression in humans to patients diagnosed with an autoimmune disease (e.g. [0102]), and exemplifies Crohn's disease as an autoimmune disease (e.g. [0018], [0040]) and PD-L1-Ig (i.e. PD-L1-Fc) fusion protein as a therapeutic form of PD-L1 (e.g. [0141]), thereby anticipating claims 14-16.
9. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
10. Claims 25, 29-30, 35-36, and 38-39 are rejected under 35 U.S.C. 103 as being unpatentable over the combined teachings of Mozaffarian et al. (US 20090110667), Cheung et al. (US 20110171314), and Powell et al. (US 20160235683).
Claim 25 is directed to a chitosan derivative nanoparticle comprising an encapsulated expression vector comprising a nucleic acid encoding a human PD-L1 polypeptide for localized intestinal expression, wherein the nucleic acid comprises a plurality of synonymous substitutions compared to the wild-type PD-L1-encoding SEQ ID NO: 2.
As described in section 8 above, Mozaffarian teaches administering codon-optimized PD-L1-Fc-encoding nucleic acid to treat Crohn's disease (e.g. [0018], [0040], [0102], [0141]). Mozaffarian further teaches that methods of administration include oral administration using known formulations allowing the therapeutic agents to reach the intestines, without being significantly inactivated by gastric fluids in the stomach (e.g. [0174]).
Although Mozaffarian does not exemplify encapsulating expression vectors in a chitosan derivative nanoparticle, the advantages of doing so for oral delivery of nucleic acid-based therapies were known and appreciated in the art before the effective filing date of the claimed invention. For example, Cheung describes a working example demonstrating that oral administration of chitosan-packaged DNA particles comprising non-viral expression vector results in successful transfection and expression of the encoded proteins in gut mucosal cells in vivo (e.g. [0198], [0462]-[0465], and Fig. 14).
Powell provides further motivation for using nanoparticles to specifically deliver PD-L1 expression vectors to intestinal immune cells. Powell teaches that intestinal M (microfold) cells sample nanoparticles from the gut lumen and transport them to underlying immune cells (e.g. [0008], [0009]), and proposes that synthetic nanoparticles can be used for transporting therapeutic biological molecules for uptake by intestinal immune cells (e.g. [0012]). Powell further teaches that intestinal immune cells in Crohn's disease patients express little or no PD-L1, in contrast to the corresponding cells of healthy subjects (e.g. [0034], [0046], [0124], [0230], and Fig. 8), and proposes treating inflammatory bowel disease with agents which upregulate PD-L1 expression in intestinal cells (e.g. [0034], [0121]-[0148]), in particular nucleic acids and vectors encoding PD-L1 (e.g. [0137]-[0142]). Using nanoparticles for delivering these agents presents the advantage of targeting the very intestinal lymphoid follicle cells that are deficient in PD-L1 expression (e.g. [0127]).
To conclude, the cited references, considered as a whole, provide both motivation and expectation of success in encapsulating PD-L1 expression vector in chitosan derivative nanoparticles for directing localized intestinal expression of the protein for treatment of Crohn's disease. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
11. Claims 14, 18, 25, and 31-33 are rejected under 35 U.S.C. 103 as being unpatentable over Mozaffarian et al. (US 20090110667), Cheung et al. (US 20110171314) and Powell et al. (US 20160235683), and further in view of Sung et al. (US 20170189476).
The relevant teachings of Mozaffarian, Cheun, and Powell are described in section 10 above.
Sung teaches that PD-L1-Ig protein obtained by fusing IgG1 Fc to PD-L1 is effective in models of inflammatory bowel disease and colitis (e.g. the Abstract; [0005], [0016], [0052]), and can be administered to the subject in the form of a nucleic acid encoding the fusion protein, within an expression vector such as a viral vector of a recombinant bacterial or eukaryotic plasmid, which may be administered by an oral or rectal route (e.g. [0145]-[0149]). PD-L1 can be linked to the Fc domain via a linker (e.g. [0079]), which may consist of Gly and Ser, for example comprise GSGGGGSGGGS (e.g. [0087]), which comprises the (GGGGS)1 sequence (underlined) recited in instant claim 32.
A fusion of PD-L1 to IgG1 Fc can target activated T cells to suppress their activity in autoimmune diseases and organ transplantation (e.g. [0005]); however, human IgG1 causes CDC and ADCC, which must be reduced for the fusion to be therapeutically useful (e.g. [0007], [0008]). Sung teaches several modified Fc variants including, for example, SEQ ID NO: 44 (e.g. claim 15), which comprises amino acid substitutions A327G, A330S and P331S, recited in instant claim 33. These teachings provide both motivation and expectation of success in using an Fc fragment of IgG1 isotype with substitutions which reduce CDC and ADCC for treating inflammatory bowel disease.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
12. Claims 25-27 are rejected under 35 U.S.C. 103 as being unpatentable over Mozaffarian et al. (US 20090110667), Cheung et al. (US 20110171314) and Powell et al. (US 20160235683), further in view of Baker et al. (US 20120295355) and Artursson et al. (US 20050164964).
The relevant teachings of Mozaffarian, Cheun, and Powell are described in section 10 above.
Baker teaches that derivatizing chitosan with arginine improves the efficiency of transfection and resulting protein expression (e.g. Examples 1-11). Similarly, Artursson teaches the advantages of chitosan containing covalently linked glucose for non-viral gene delivery (e.g. the Abstract, [0058], [0080]-[0087], claim 7). These teachings provide both the motivation and the expectation of success in utilizing chitosan coupled with arginine and glucose for delivery of PD-L1 encoding nucleic acids.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention, as evidenced by the references, especially in the absence of evidence to the contrary.
13. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP §§ 706.02(l)(1) - 706.02(l)(3) for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
14. Claims 14-16, 18-19 and 25-39 are rejected on the ground of nonstatutory double patenting as being unpatentable over the claims of U.S. Patent No. 11603398.
Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims are anticipated by or obvious over the claims of US ‘398.
Claim 1 of US ‘398 recites a method for treating inflammatory bowel disease, ulcerative colitis, or Crohn's disease comprising administering to the gastrointestinal tract of a patient an expression vector comprising SEQ ID NO: 3 or SEQ ID NO: 4 for localized intestinal expression of human PD-L1, wherein the expression vector is encapsulated in a chitosan derivative nanoparticle,
SEQ ID NOS: 3 and 4 are codon-optimized (i.e. comprise synonymous substitutions) and possess all the features recited in instant claims 15-16, 18, 29-33, and 35-36. These features are also recited in claims 2-6 and 8-9 of US ‘398.
Instant claims 26-27 would have been obvious over the claims of US ‘398 for the same reasons as presented in section 12 above.
15. The following prior art is cited of record but not presently relied upon: US Pat. Pubs No.
20110178030,
20140341933,
20120076805,
20160220636,
20180214487,
20100035973,
20150139994,
20130130965.
20160304851,
20120282343,
20120164174.
16. Conclusion: no claim is allowed.
17. Any inquiry concerning this communication or earlier communications from the examiner should be directed to ILIA I OUSPENSKI whose telephone number is (571)272-2920. The examiner can normally be reached 8:30 AM – 5 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Daniel Kolker can be reached at 571-272-3181. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ILIA I OUSPENSKI/ Primary Examiner, Art Unit 1644